Fatigue occurs in up to 80% of cancer patients undergoing radiation or chemotherapy and is significantly debilitating. Our lab studies skin signaling which mediates UV induced pigmentation. UV damages DNA in keratinocytes, thereby stabilizing p53 which stimulates expression of pro-opiomelanocortin (POMC). In turn, POMC is cleaved into several peptides, one of which, Melanocyte Stimulating Hormone, activates pigmentation. Another POMC derived peptide is 2-endorphin. We have observed elevations in systemic blood levels of 2-endorphin following repeated low-dose UV radiation. Multiple studies suggest that UV may trigger opiate-like addictive behaviors, which are likely mediated by this UV-POMC-2endorphin axis. We believe the origins of this behavioral linkage may relate to evolutionary advantages of sun-seeking behaviors to maintain UV derived cutaneous vitamin D synthesis. Since control of this pathway is exerted by p53 (DNA damage sensor), we tested whether non-UV DNA damage triggers, especially ionizing radiation or certain chemotherapeutics, may also trigger 2-endorphin synthesis and found that they do. Fatigue is a prominent opiate phenotype, and one which accompanies the majority of cancer patients undergoing therapies which are known to potently induce p53. We observed elevations in blood 2-endorphin following either large single doses or repeated fractionated doses of either UV or ionizing radiation, as well as adriamycin in rodents. As with tanning/pigmentation, this 2-endorphin response is absent in p53-/- mice. Using fractionated tail ionizing irradiation (simulating cancer radiation therapy) we observed elevations in blood 2-endorphin after several weeks. Quantitative rat actimetry measurements revealed major locomotor depression, indicative of severe fatigue, which precisely correlated temporally with 2-endorphin blood elevations. Most importantly, the locomotor/fatigue changes were rapidly and fully reversed by treatment with the 5-opiate receptor antagonist naloxone. A role for 2-endorphin in human radiation fatigue would be particularly important because drugs which modulate this pathway are readily available to apply to patients. We propose to expand these studies preclinically and clinically in the following Specific Aims: 1) carry out a prospective clinical trial to examine blood 2-endorphin levels together with self-assessments of fatigue and other opiate-related behavioral phenotypes using validated questionnaire instruments in humans undergoing chemotherapy and/or radiation therapy for breast cancer, 2) dissect parameters of this pathway pre-clinically, specifically testing a) radiation dose-response, b) relationship between fatigue and radiation skin toxicity, c) electron beam radiation, d), adriamycin induced fatigue (naloxone reversibility), e) crosstalk/impact of vitamin D deficiency, and f) optimization of naltrexone schedule/dosing. These mechanism-based studies may set the stage for rapid application of opiate pathway modulation using existing drugs, as a targeted therapeutic approach for this major quality of life challenge in cancer patients.